1. Field of the Invention
This invention relates to large size, small surface area granular crystals of potassium bicarbonate particularly useful as active ingredients of pharmaceutical oral dosage forms for potassium supplementation and for the treatment of degenerative bone or cardiovascular diseases, e.g., osteoporosis and hypertension, and to a process for the preparation of such crystals.
Potassium bicarbonate is a well-known commodity of commerce having various uses, e.g., in baking powders, as an effervescent salt in soft drinks, as a fire-extinguishing agent, and in various pharmaceutical applications, for example, in the treatment of excess acidity. Presently, potassium bicarbonate is available in commercial quantities in the form of very fine crystals or agglomerates, which are irregularly shaped, have rough surfaces, exhibit poor packing and flow characteristics and may be subject to dusting or caking problems.
One current commercially available potassium bicarbonate product, marketed as "Coarse Granular Potassium Bicarbonate" by Armand Products Co., Princeton, N.J., U.S.A., comprises irregularly shaped, rough-surfaced crystals with few agglomerates, which has a mean particle size of about 180 microns, essentially no individual crystals larger than 300 microns and a B.E.T. specific surface area of 0.06 m.sup.2 /gram. A second commercial product, available from Mallinckrodt Specialty Chemicals Co., St. Louis, Mo., U.S.A., as "Potassium Bicarbonate USP Granular TAC", comprises similar irregularly shaped, rough-surfaced and non-agglomerated crystals and has a mean particle size of about 180 microns with essentially no individual crystals larger than 420 microns and a B.E.T. surface area of 0.02 m.sup.2 /gram. A third currently available product, "Alphapur Granular Potassium Bicarbonate" produced by SCPA of Paris, France, is a rough-surfaced, largely agglomerated product having a mean particle size of about 300 microns and a B.E.T. surface area of 0.02 m.sup.2 /gram. If separated by screening into varying size fractions, about 10% of this product comprises agglomerates having sizes within the range of 600 to 850 microns with a B.E.T. surface area of 0.018 m.sup.2 /gram.
It has recently been proposed to use potassium bicarbonate as an active ingredient for the treatment of osteoporosis or hypertension. See Morris et al U.S. Pat. No. 5,171,583 granted Dec. 15, 1992, and PCT Published Application No. PCT/US89/04771. The potassium bicarbonate crystals of the present invention are particularly suitable for oral dosage forms useful in this last mentioned application. They are also useful in other applications, e.g., for agricultural uses, or where it is important to avoid dust formation or caking.
The effective oral dosage of potassium bicarbonate in the treatment of osteoporosis or hypertension is about 40-400 mmoles, preferably about 40-250 mmoles, per 70 kg patient weight per day. In a particularly preferred embodiment, the potassium bicarbonate is administered at a dose of 60 mmoles (6 grams) per day. When, for example, the potassium bicarbonate is administered in the form of four tablets daily, each such preferred oral dosage form should incorporate 1.5 grams of the potassium bicarbonate. Since potassium bicarbonate has a bitter taste and is irritating to the gastrointestinal mucosa, the potassium bicarbonate must be coated with a controlled release coating masking its taste and facilitating controlled release in the G.I. tract over an extended time period.
For ease of swallowing, solid dosages of drugs intended for chronic administration to humans should not possess total volumes of more than about one milliliter. When 1.5 grams of current commercially available, small particle size granular (unagglomerated) potassium bicarbonate particles are tabletted, with a release coating having a density of about 1/gram/ml., the resulting dosage form has a significantly greater volume. Clearly, such a tablet would be hard to swallow and would not meet with good patient acceptance, particularly in any product used in the treatment of a chronic disease. It has thus been found critical, in accordance with the present invention, to provide potassium bicarbonate crystals having markedly greater particle sizes and markedly decreased specific surface areas as compared with currently available potassium bicarbonate crystalline products.
Various processes have been described in the patent literature for preparing potassium bicarbonate. None of the references which have been noted make any specific mention of the formation of large particle size, small surface area potassium bicarbonate crystals. See, for example, U.S. Pat. Nos. 1,477,086; 2,013,977; 2,543,658; 2,768,060; 3,141,730; 3,347,623; and 4,919,910. On the other hand, a number of procedures have been specifically described in the patent literature for producing coarse crystals of sodium bicarbonate or other salts. See, for example, U.S. Pat. Nos. 2,773,739; 2,792,283; 2,926,995; 3,647,365; 3,855,397; 3,870,784; EP Published Application No. 395,134 [sodium bicarbonate]; U.S. Pat. No. 2,721,209 [ethylene diamine tartrate]; and U.S. Pat. No. 5,085,670 [potassium chloride]. Crystallization is, however, an empirical art and procedures utilized for growing crystals of one substance often do not work for another.
Thus, procedures described in the literature for producing coarse sodium bicarbonate crystals have not been found useful for forming large, pure potassium bicarbonate crystals. Conversely, the procedures described below for the formation of large, low surface area potassium bicarbonate crystals have not been as successful in forming large sodium bicarbonate crystals since the latter material tends to nucleate during crystallization with the formation of crystals having minute particle sizes. In addition, crystal growth modifiers (which may be employed in conventional commercial manufacturing operations) may not be suitable in the production of potassium bicarbonate utilized in pharmaceutical products due to the stringent purity requirements for such products.
It is, accordingly, among the objects of the present invention to provide large size, small surface area potassium bicarbonate crystals which may be efficiently produced in commercial quantities and which may be formulated in orally administrable dosage forms useful for pharmaceutical applications and, in particular, in dosage forms suitable in the treatment of osteoporosis or hypertension. A further object of the invention is the provision of a process for the preparation of such large potassium bicarbonate crystals which may be efficiently utilized in the commercial production of such dosage forms. Other objects and advantages of the invention will be apparent from the following description.